Method of manufacturing microneedle structures using soft lithography and photolithography

ABSTRACT

A method for manufacturing microneedle structures is disclosed using soft lithography and photolithography, in which micromold structures made of a photoresist material or PDMS are created. The micromold manufacturing occurs quite quickly, using inexpensive materials and processes. Once the molds are available, using moldable materials such as polymers, microneedle arrays can be molded or embossed in relatively fast procedures. In some cases a sacrificial layer is provided between the forming micromold and its substrate layer, for ease of separation. The microneedles themselves can be solid projections, hollow “microtubes,” or shallow “microcups.” Electrodes can be formed on the microneedle arrays, including individual electrodes per hollow microtube.

TECHNICAL FIELD

The present invention relates generally to microneedle arrays and isparticularly directed to a method for manufacturing microneedlestructures using soft lithography and photolithography. The invention isspecifically disclosed as a method of manufacturing microneedles bycreating micromold structures made of a photoresist material or PDMS,and in some cases using a sacrificial layer for ease of separation froma substrate layer.

BACKGROUND OF THE INVENTION

Topical delivery of drugs is a very useful method for achieving systemicor localized pharmacological effects, although there is a main challengeinvolved in providing sufficient drug penetration across the skin. Skinconsists of multiple layers, in which the stratum corneum layer is theoutermost layer, then a viable epidermal layer, and finally a dermaltissue layer. The thin layer of stratum corneum represents a majorbarrier for chemical penetration through the skin. The stratum corneumis responsible for 50%-90% of the skin barrier property, depending uponthe drug material's water solubility and molecular weight.

An alternative to the use of hypodermic needles for drug delivery byinjection is disclosed in U.S. Pat. No. 3,964,482 (by Gerstel), in whichan array of either solid or hollow microneedles is used to penetratethrough the stratum corneum and into the epidermal layer. Fluid isdispensed either through the hollow microneedles or through permeablesolid projections, or perhaps around non-permeable solid projectionsthat are surrounded by a permeable material or an aperture. A membranematerial is used to control the rate of drug release, and the drugtransfer mechanism is absorption.

Other types of microneedle structures are disclosed in WO 98/00193 (byAltea Technologies, Inc.), and in WO 97/48440, WO 97/48441, and WO97/48442 (by Alza Corp.). In addition, WO 96/37256 discloses anothertype of microblade structure.

The use of microneedles has one great advantage in that intracutaneousdrug delivery or drug sampling can be accomplished without pain andwithout bleeding. As used herein, the term “microneedles” refers to aplurality of elongated structures that are sufficiently long topenetrate through the stratum corneum skin layer and into the epidermallayer. In general, the microneedles are not to be so long as topenetrate into the dermal layer, although there are circumstances wherethat would be desirable. Since microneedles are relatively difficult tomanufacture, it would be an advantage to provide methodologies forconstructing microneedles that are made from various types of micromoldsthat can be manufactured relatively quickly. The use of metallic moldsor semiconductor molds is possible, but such structures usually take arelatively long period of time for construction. On the other hand, ifthe molds are made of a polymer or other type of plastic (or othermoldable) material, then such mold structures can be made relativelyquickly and with much less expense.

SUMMARY OF THE INVENTION

Accordingly, it is an advantage of the present invention to provide amethod for fabricating microneedles using photolithography and softlithography techniques, which allow for quick manufacturing of bothmicromolds and usable microneedle structures.

It is another advantage of the present invention to provide a method forfabricating microneedles in which a photoresist material is applied in asingle layer, or in multiple layers, and patterned via photolithography,thereby either creating a microneedle structure that can be directlyused, or creating micromold structure that can be used with moldablematerial such as polymers to manufacture the microneedle structures.

It is a further advantage of the present invention to provide a methodfor fabricating microneedles in which soft lithography is used to createmicroneedle structures that can be directly used, or to create micromoldstructures that can be used with moldable material such as polymers tomanufacture the microneedle structures, in which a moldable material hasits shape formed, at least in part, by another relatively “soft”material—e.g., something other than a metal.

It is still another advantage of the present invention to provide amethod for fabricating microneedles in which soft lithography is used tocreate microneedle structures that can be used to create flexiblemicromold structures that can be used with moldable material such aspolymers to manufacture the microneedle structures, in which theresulting microneedle array is either concave or convex in overallshape.

It is yet a further advantage of the present invention to provide amethod for fabricating microneedles in which photolithography and/orsoft lithography is used to create micromold structures, and in which asacrificial layer of material is dissolved or decomposed to separate themicromold structures from a substrate.

It is still a further advantage of the present invention to provide amethod for fabricating microneedles in which photolithography and/orsoft lithography is used to create microneedle structures, and furthercoating a surface of the microneedle structures using a vapor depositionprocess, and/or another coating process such as: electroplating,electrodeposition, electroless plating, sputtering, or plasmadeposition.

It is yet another advantage of the present invention to provide a methodfor fabricating microneedles in which photolithography and/or softlithography is used to create master structures, and further using amicroembossing or molding process to manufacture microneedle structures.

It is still another advantage of the present invention to provide amethod for fabricating microneedles in which photolithography and/orsoft lithography is used to create microneedle structures, and furthercreating electrodes on the microneedle structures, either in “bands” ofelectrically conductive material that each encompass multiplemicroneedles, or in individual small electrically conductive structuresthat run inside a single hollow microneedle.

It is a further advantage of the present invention to provide a methodfor fabricating microneedles in which photolithography and/or softlithography is used to create microneedle structures, in which the tipsof the microneedles are either hardened or made more flexible, or inwhich the base (or substrate) of the microneedle array is made moreflexible, or in which the microneedles break away from the base(substrate) of the array after application to skin, thereby leavingbehind hollow microtubes that protrude through the stratum corneum.

Additional advantages and other novel features of the invention will beset forth in part in the description that follows and in part willbecome apparent to those skilled in the art upon examination of thefollowing or may be learned with the practice of the invention.

To achieve the foregoing and other advantages, and in accordance withone aspect of the present invention, a method for fabricatingmicroneedles is provided including steps of: (a) providing a substratethat includes multiple microstructures; (b) coating the substrate with alayer of a first moldable material that takes the negative form of themicrostructures, and hardening the first moldable material; (c)separating the hardened first moldable material from the substrate, andcreating a micromold from the hardened first moldable materialcontaining the microstructures; and (d) applying a second moldablematerial onto the micromold, allowing the second moldable material toharden using a soft lithography procedure, then separating the hardenedsecond moldable material from the micromold, thereby creating amicroneedle structure from the hardened second moldable material havingthe three-dimensional negative form of the microstructures of thepatterned micromold.

In accordance with another aspect of the present invention, a method forfabricating microneedles is provided including steps of: (a) providing asubstrate material; (b) coating the substrate material with at least onelayer of a photoresist material, and patterning the photoresist materialwith multiple microstructures by use of a photolithography procedure;and (c) separating the patterned photoresist material from the substratematerial, thereby creating a microneedle structure from the patternedphotoresist material containing the microstructures.

In accordance with a further aspect of the present invention, a methodfor fabricating microneedles is provided including steps of: (a)providing a substrate material; (b) coating the substrate material withat least one layer of a photoresist material, and patterning thephotoresist material with multiple microstructures by use of aphotolithography procedure; (c) coating the patterned photoresistmaterial with a layer of moldable material that takes the negative formof the microstructures, and allowing the moldable material to hardenusing a soft lithography procedure, then separating the hardenedmoldable material from both the patterned photoresist material and thesubstrate material; and (d) coating at least one surface of theseparated hardened moldable material by use of a vapor depositionprocedure.

In accordance with yet a further aspect of the present invention, amethod for fabricating microneedles is provided including steps of: (a)providing a substrate material; (b) coating the substrate material withat least one layer of a photoresist material, and patterning thephotoresist material with multiple microstructures by use of aphotolithography procedure; (c) applying a first moldable material ontothe patterned photoresist material/substrate and allowing the firstmoldable material to harden using a soft lithography procedure, thenseparating the hardened first moldable material from the patternedphotoresist material/substrate to create a microstructure; and (d)molding or embossing a second moldable material onto the microstructure,and after hardening of the second moldable material, separating thehardened second moldable material from the microstructure, therebycreating a microneedle structure from the hardened second moldablematerial having the three-dimensional negative form of themicrostructure.

In accordance with still a further aspect of the present invention, amethod for fabricating microneedles is provided including steps of: (a)providing a substrate material; (b) coating the substrate material withat least one layer of a photoresist material, and patterning thephotoresist material with multiple microstructures by use of aphotolithography procedure, such that the patterned photoresist materialcomprises the microstructures; (c) coating the substrate with a layer ofmoldable material that takes the negative form of the microstructures,and hardening the moldable material by a soft lithography procedure; (d)separating the hardened moldable material from the substrate, therebycreating a mask; (e) providing a microneedle array structure havingmultiple individual protrusions extending from a base; and (f)positioning the mask proximal to the microneedle array structure andapplying an electrically conductive substance through the mask onto asurface of the microneedle array structure, thereby creating at leastone pattern of electrically conductive pathways on the surface.

In accordance with still another aspect of the present invention, amicroneedle structure is provided which comprises a longitudinal elementhaving a first end and a second end, in which the longitudinal elementhas a side wall extending between the first end and the second end; andthe side wall also has at least one external channel running betweensubstantially the first end and the second end.

Still other advantages of the present invention will become apparent tothose skilled in this art from the following description and drawingswherein there is described and shown a preferred embodiment of thisinvention in one of the best modes contemplated for carrying out theinvention. As will be realized, the invention is capable of otherdifferent embodiments, and its several details are capable ofmodification in various, obvious aspects all without departing from theinvention. Accordingly, the drawings and descriptions will be regardedas illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings incorporated in and forming a part of thespecification illustrate several aspects of the present invention, andtogether with the description and claims serve to explain the principlesof the invention. In the drawings:

FIGS. 1A-1F are diagrammatic views in cross-section that illustrate someof the process steps for manufacturing polymeric microneedles by replicamolding, in which PDMS molds are prepared by employing a photoresistmaster.

FIGS. 2A-2E are diagrammatic views in cross-section that illustrate someof the process steps for manufacturing polymeric microneedles by replicamolding, in which PDMS molds are made utilizing a silicon specimen thatwas fabricated by deep reactive ion etching (DRIE).

FIGS. 3A-3E are diagrammatic views in cross-section showing the stepsemployed to construct microneedle arrays made of a photoresist material,in which photolithography is used on a substrate that is coated withsilicon oxide.

FIGS. 4A-4E are diagrammatic views in cross-section showing the stepsemployed to construct microneedle arrays made of a photoresist material,in which photolithography is used on a substrate that is coated withPDMS.

FIGS. 5A-5F are diagrammatic views in cross-section showing the varioussteps employed to fabricate hollow microneedles using depositiontechniques, in which metallic hollow microneedles are made byelectroplating on a PDMS structure.

FIGS. 6A-6E are diagrammatic views in cross-section showing the varioussteps employed to fabricate hollow microneedles using depositiontechniques, in which polymeric hollow microneedles are constructed byelectrodeposition on PDMS posts.

FIGS. 7A-7B, 7X-7Z are diagrammatic views in cross-section showing someof the structural steps used in fabricating arrays of detachablemicrotubes, in which photolithography is used on a wafer coated withPDMS.

FIGS. 8A-8D, 8X-8Z are diagrammatic views in cross-section showing someof the structural steps used in fabricating arrays of detachablemicrotubes, in which photolithography on an oxidized silicon wafer.

FIGS. 9A-9G are diagrammatic views in cross-section illustrating some ofthe structural steps employed to fabricate hollow microneedles usingdeposition techniques, in which metallic hollow microneedles are made byelectroplating on a PDMS structure.

FIGS. 10A-10G are diagrammatic views in cross-section illustrating someof the structural steps employed to fabricate hollow microneedles usingdeposition techniques, in which polymeric hollow microneedles areconstructed by electrodeposition on PDMS posts.

FIGS. 11A-11K are diagrammatic views in cross-section showing thestructural steps utilized to manufacture hollow microneedles usingcomplimentary PDMS molds.

FIGS. 12A-12G are diagrammatic views in cross-section of some of thestructural steps employed to fabricate polymeric hollow microneedles byreplica molding of multilayer patterns.

FIG. 12H is a perspective view of a PDMS replica molding, as seen inFIG. 12E.

FIGS. 12I-12J are further diagrammatic views in cross-section of some ofthe structural steps employed to fabricate polymeric hollow microneedlesby replica molding of multilayer patterns.

FIGS. 13A-13C, 13F-13I, are perspective views of some of the structuralsteps used to construct electrodes inside hollow microneedles.

FIGS. 13D-13E are magnified plan views of the individual electrodepatterns used in the photolithography steps of FIGS. 13B and 13C.

FIG. 13J is a perspective view in partial cross-section and magnified ofa single hollow microneedle having an internal electrode, as seen inFIG. 13I.

FIG. 14 is a plan view of a microneedle array that contains electrodebands.

FIGS. 15A-15L are diagrammatic cross-sectional views of structural stepsused to fabricate sharp tipped microneedles.

FIGS. 16A-16E are perspective views showing the structural stepsutilized to manufacture convex or concave microneedles using flexiblemolds.

FIG. 17 is a perspective view of a solid microneedle having an externalchannel along its elongated side wall.

FIG. 18 is a top, elevational view of multiple solid microneedles eachhaving two external channels along their elongated side wall.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to the present preferred embodimentof the invention, an example of which is illustrated in the accompanyingdrawings, wherein like numerals indicate the same elements throughoutthe views.

Using the principles of the present invention, polymeric microneedlescan be fabricated by replica molding in which PDMS molds are preparedusing a photoresist master. Alternatively, polymeric microneedles can bemade by replica molding in which PDMS molds are made utilizing a siliconwafer that is fabricated by deep reactive ion etching or any otheretching technique known by those skilled in the art. In both cases, thePDMS material becomes a negative replica which is used as a mold thatcan be later filled with a prepolymer material that will itself becomean array of microneedles. Both solid and hollow microneedles can be madeby the techniques of the present invention.

Although the term “PDMS” is used throughout this patent document in verymany places, it will be understood that other materials could instead beused with the present invention in lieu of PDMS, depending upon themicrofabrication process of choice. In a replication molding procedure,one could use any moldable material having low surface energy, and theconsequent poor adhesion with most substrates. For sacrificial layers,highly reactive polymers or other materials that are soluble in organicor inorganic solvents could replace PDMS. Furthermore, silanization willnot generally be necessary if totally inert elastomers are used forreplication (e.g., fluorinated polymers). PDMS™ is manufactured by DowCorning Corporation of Midland, Mich.

In the situation where a photoresist material is used, this material ispatterned by use of photolithography techniques, and the patternedstructure is used to create the PDMS negative replica. The precisedesign for the transparency mask used in the photolithography proceduresutilizes a microfabrication method that is based on a rapid prototypingtechnique which uses design software and a high resolution printer;however, masks prepared using the traditional methodologies known bythose skilled in the art can also be implemented using this process. Thepresent invention makes good use of photolithography, generally usingSU-8 photoresist materials, and a combination of replica molding usingsoft lithography, electroplating or microembossing processes. Suchprocesses are less expensive and have quicker turnaround time (e.g.,less than twenty-four hours) than those previously known in the art forthe fabrication of microneedles.

Although the term “SU-8” is used throughout this patent document in verymany places as an example of photoresist material, it will be understoodthat other materials could instead be used in lieu of SU-8, which is aparticular brand of photoresist manufactured by MicroChem Corporation ofNewton, Mass. SU-8™ has some particularly desirable characteristics, inthat as a photoresist it can produce a film thickness greater than orequal to thirty (30) microns. Of course, if the designer wishes toproduce a photoresist film having a thickness less than 30 microns, thencertainly other photoresist materials could be used. Moreover,photoresist materials other than SU-8 that produce film thicknessesgreater than 30 microns may be available, or may become available, andthose could perhaps be advantageously used in the present invention.

The present invention not only uses photolithography for patterningcertain structures, but also uses “soft lithography” for creatingstructures in three dimensions using molds made of a polymer material orsimilar non-metallic material. The soft lithography is a methodology inwhich all members involved share a common feature in that they use apatterned elastomer as the mask, stamp, or mold. (See, “SoftLithography,” by Younan Xia and George M. Whitesides,” Angew. Chem. Int.Ed. 1998.37.550-575.) This elastomeric stamp or mold transfers itspattern to the “moldable material” which can comprise flexible organicmolecules or other materials, rather than rigid inorganic materials nowcommonly used in the fabrication of microelectronic systems. In thepresent invention, such soft lithography processes are utilized inalmost every methodology for creating an array of microneedles.

Professor George Whitesides and colleagues have used soft lithography innumerous microfabrication processes, including: fabrication of carbonmicrostructures utilizing elastomeric molds (see published patentapplication, WO 98/34886 A1), etching of articles via microcontactprinting (see WO 98/34886 A1), microcontact printing of catalyticcolloids (see WO 97/34025), fabrication of small coils and bands bypatterning cylindrical objects with patterns of self-assembledmonolayers (see WO 97/44692 and WO 97/07429), formation of articles viacapillary micromolding (see WO 97/33737), and the utilization ofelastomeric masks to fabricate electroluminescent displays (see WO99/54786).

Silicon masters fabricated using conventional silicon micromachiningtechnologies such as deep reaction ion etching, or structures preparedusing LIGA processes, also can be employed for replica molding ofmicroneedles. Such silicon masters will generally require more time increating the replica molds as compared to the microfabrication methodsof the present invention that create mold replicas using photoresist orPDMS (or similar) materials.

The methodologies described below can be used to manufacture solid,partially hollow, or totally hollow microneedles, and such microneedlescan be made of electrodepositable metals, thermoplastics, or polymersthat cure using heat energy, light energy, or by the addition of aninitiator under normal conditions. When photolithography techniques areused, then the light energy is generally used for both patterning andcuring the materials, although the curing methodologies can certainlyinvolve other types of energy sources than light.

As noted above, the fabrication techniques described in this documenthave quicker turnarounds than many others that have been described inthe prior art for the fabrication of microneedles. The replica mold canoften be made of PDMS material, which is formed into the appropriateshapes by use of a silicon or metallic structure that has been entirelyformed to the proper shape, or a silicon wafer structure that haspredetermined protrusions that are made of a photoresist material, inwhich the photoresist was patterned using photolithography techniques.Once the PDMS mold negative replica has been formed, it can be filledwith a prepolymer or other type of moldable material, in which theprepolymer or other material becomes the actual array of microneedles.The prepolymer is then cured in a soft lithography process step.

An alternative fabrication technique is to begin with a layer ofphotoresist material that is separated from a silicon wafer or othersubstrate material by a “sacrificial layer,” made of a material such asPDMS or silicon oxide. One fabrication technique is to place a firstlayer of photoresist that is cured without using a mask, and thenplacing a second layer of photoresist that is patterned usingphotolithography or other patterning techniques. The first photoresistlayer later becomes the substrate or base of a microneedle array, whilethe second layer of photoresist material later becomes the actualprotrusions that create the microneedle structures, either solid orhollow. Once the photoresist layers are completely patterned and cured,the sacrificial layer is then dissolved or otherwise decomposed, therebyseparating the silicon wafer initial substrate from the microneedlearray.

As noted above, the fabrication procedures can be used to make eithersolid or hollow microneedles. If hollow microtubes are to be createdfrom a silicon wafer having a photoresist top layer, then the top layerof photoresist is patterned as an array of hollow microtubes usingphotolithography techniques. After that has occurred, the“wafer/patterned photoresist” is silanized and coated with a PDMSmaterial that is cured in a soft lithography process. Once the PDMS hasbeen cured, it is separated from the original silicon wafer/substrateand patterned photoresist combination, thereby producing a negativereplica comprising PDMS. The negative replica is then filled with aprepolymer material that is cured with electromagnetic energy or heatenergy in a soft lithography process, and once cured the prepolymer isdetached from the PDMS mold replica, thereby forming an array of hollowmicroneedles. At this point, the microneedles may not be completelyhollow, as the through-holes only go so far into the photoresistmaterial. Of course, these “microcups” can be opened by laser ablation,or some other type of microfabrication technique.

An alternative methodology for creating hollow microneedles or“microtubes” is to begin with a silicon wafer or other substratematerial, place a sacrificial layer on its top, and further place alayer of photoresist above that sacrificial layer. This first layer ofphotoresist is cured without using a mask, and then it is covered with asecond layer of photoresist that is baked to dryness. An array ofmicroneedles or “microtubes” is then formed in the second layer ofphotoresist by photolithography techniques. Once this has occurred, thesacrificial layer is dissolved or otherwise decomposed, thereby leavingbehind an array of microneedles made of the photoresist material. Atthis point, the microneedles may not be completely hollow, as thethrough-holes only go so far into the photoresist material. Of course,these “microcups” can be opened by laser ablation, or some other type ofmicrofabrication technique.

Once hollow microtubes or microcups have been formed on a silicon waferor other substrate, they can be made more detachable in skin by anapplication of an acid along the base of the outer walls of themicroneedles, to thereby etch away a small portion of the material atthe base. This will make it more likely that the microneedles can easilydetach from the main base or substrate of the microneedle array. This isuseful in situations where the microneedles are used to penetrate thestratum corneum of skin, and then have the array base or substrateremoved from the skin surface. The microneedles will break away fromthat substrate/base at that time, thereby leaving hollow microneedleswithin the stratum corneum. Such microneedles will stay embedded in thestratum corneum until the stratum corneum is renewed, thereby providinga location on the skin where liquids temporarily can be introduced orextracted.

Break-away microneedles can also be made by use of PDMS materials orother coatings that have poor adhesion with photopolymers as thesubstrate and a photoresist material that makes up the actualmicroneedles. Such photoresist hollow microneedles would likely breakaway from the PDMS substrate/base of the microneedle array uponapplication into the stratum corneum of skin. This would then leavebehind multiple such hollow microneedles in the stratum corneum once thearray's base/substrate is removed.

The present invention also provides procedures that can fabricate hollowmicroneedles using deposition techniques. Both metallic hollowmicroneedles and polymeric hollow microneedles can be constructed insuch a manner. The metallic hollow microneedles are made by creating aPDMS negative replica that is then electroplated onto the microneedlestructure. This would typically produce “closed” microneedles, whichcould have their own usefulness, although in many cases the microneedleswill be opened to create microtubes with through-holes by use of sometype of polishing operation.

Polymeric hollow microneedles can be constructed using depositiontechniques by creating a negative PDMS replica and electrodepositing apolymer on “posts” or other microneedle-type structures that areconstructed from the PDMS. Once the polymer has been plated on the PDMS,the plated polymer is separated from the PDMS mold, thereby leavingbehind multiple microneedle structures that have the form of “closed”microneedles. Such microneedles can be opened to create completelythrough-hole hollow microneedles by a polishing operation.

The principles of the present invention can also be used to manufacturehollow microneedles using complimentary molds made of PDMS. In thissituation, two separate silicon wafers, for example, can be used asstarting points in which each are coated with a layer of photoresistmaterial. Using photolithography techniques, each of these wafers hasits photoresist layer patterned; in the first case holes are formed inthe photoresist layer, and in the second case posts or other similarstructures are formed in the photoresist. These patterns will becomplimentary, as will be seen below. Both wafers are now silanized andcoated with PDMS. The PDMS is cured, and once cured, the PDMS forms anegative replica that can be removed or detached from their respectivesilicon wafers. The photolithography stage forms both holes and “posts”that are complimentary to one another, and therefore, the two negativereplicas made of PDMS are also complimentary. One of these negativereplicas is turned upside down, a layer of prepolymer is then placed ontop of that “turned-around” PDMS negative replica, and then the secondnegative replica is placed on top of the prepolymer, thereby sandwichingthe prepolymer in place. The prepolymer is now cured and the two PDMSmolds are detached, thereby leaving behind a separate polymer structure.If the shape formed “closed” hollow microneedles, then the closed end ofthese microneedles can be opened by use of some type of finishing orpolishing procedure.

Multiple layers of patterns can also be used with the principles of thepresent invention to create polymeric microneedles, either solid orhollow, as desired. A first layer of photoresist is placed on a siliconwafer or other substrate structure, and holes or other similar patternsare formed in the photoresist by photolithography techniques. A secondlayer of photoresist is then coated onto this structure, and using asecond photolithography procedure, microneedle forms can be made,including hollow tube microneedles. This structure is now silanized, anda PDMS negative replica is formed based upon this pattern. The PDMS nowbecomes a mold itself, and a polymer material can be placed onto thePDMS negative replica and cured or embossed, thereby forming an array ofmicroneedle structures. If the microneedles form “closed” hollowmicroneedles, then the closed ends can be removed by polishing or othertype of finishing procedure. This would leave behind an array of hollowmicroneedles having through-holes. Polishing can be avoided by pressinga PDMS flat against the mold filled with prepolymer.

The principles of the present invention can also be used to createmicroneedles having internal electrodes. Two different initialstructures are used to create the electrode-microneedle combinations. Onone hand, a polymer microneedle array is constructed according to one ofthe processes described above, in which the microneedles are hollow withthrough-holes. The other structure consists of a silicon (or othermaterial) substrate that has a layer of photoresist material applied andpatterned using photolithography. This structure is then silanized andcoated with PDMS, which is then cured. The cured PDMS layer is thenseparated from the photoresist-substrate structure, thereby becoming amask that will be aligned with the hollow microneedles of the firststructure. Once the patterned PDMS mask is aligned with the hollowmicroneedles, metal is vapor deposited on the inside of the microneedlesin a pattern that will run through a portion of the length of the hollowmicroneedles along their inner cylindrical surfaces. Similar masks couldalso be prepared using electroplating, electroless plating,electrochemical micromachining, silicon or polymer etching.

The electrode-microneedle combination can be constructed so that eachhollow microneedle has an electrode that is electrically isolated fromeach other such hollow microneedle. Alternatively, groups ofmicroneedles can be electrically connected together by use of electrode“bands” in which a first group of multiple microneedles are electricallyconnected to a “working electrode,” a second group of multiplemicroneedles are connected to a “reference electrode,” and finally athird group of multiple microneedles are electrically connected to a“counter electrode.”

A reference electrode is not needed in a two-electrode system and,depending upon the electrochemical cell design, microneedle arrays couldbe used on structures that consist of only one electrode type, such as aworking electrode, counter electrode, or reference electrode. Theseunitary-type electrode structures could be combined in a two-electrodeor a three-electrode device. Microneedles are so small in size, that the“electrode bands” might be more useful in certain applications, and themicroneedles could be either solid or hollow.

The principles of the present invention can also be used to constructmicroneedles having a very sharp tip. This could be done by havingmultiple layers that are patterned one after the other, in which eachpattern creates a cylindrical or elliptical opening such that each loweropening is smaller in size than the next adjacent higher opening. Thiswill create a series of photoresist layers, for example, that taper downto a very small opening. When these photoresist structures are finished,they can be separated from a substrate (such as silicon), and thisseparation could be facilitated by use of a sacrificial layer ofmaterial, such as silicon oxide. Once the mold has been separated fromthe substrate, a polymer or prepolymer material to be placed on top ofthe mold and forced into the openings that taper down to the smallestopening. Each one of these tapered-down structures, when cured, willbecome a sharpened tip microneedle. After curing, the array of sharp-tipmicroneedles is separated from the photoresist mold.

Other types of alternative structures are available when using theprinciples of the present invention. For example, the base material ofthe microneedle array can be made from a first structural material,while the microneedles themselves can be made of a second structuralmaterial. This allows design freedom to create hydrophobic-hydrophiliccombinations and controlled adhesion of the needles to the base. Anotheralternative structure is to chemically modify the microneedles to changetheir properties, such as treatment of silicon microneedles withsilanizing reagents to derivatize the surfaces. A further alternativestructural treatment is the use of a plasma treatment of epoxy or otherpolymeric microneedles that impart different surface properties (thatwould affect the hydrophobic or hydrophilic properties). The use ofplasma treatment, or chemically modifying the microneedles, can occur atthe molecular level, and such processes are commonly referred to as“surface modification” of structures.

Another alternative construction is to incorporate carbon fibers orother composite materials into epoxy microneedles or polymericmicroneedles, as well as their substrates, in order to make thesubstrates and/or microneedles more rigid. Certainly the use ofcomposite materials or carbon fibers could reinforce the microneedlesthemselves to make them more rigid. Alternatively, such substrates couldbe made more flexible, including the use of micro channels and groovesin the substrate. It may be likely that the microneedles themselves areto remain rigid in such a structure.

A further alternative construction of microneedles is to make them moreflexible, in which the microneedles are rigid enough to break skin, butstill have a certain amount of flexibility. This could be used insituations where the microneedles are to penetrate the skin and be heldin place for a relatively long period of time. This could be used forcontinuous monitoring and/or dispensing systems. It would be anadvantage to provide such flexible microneedles that would be virtuallyunbreakable while being used in such circumstances.

Another alternative construction is to place a metal coating over themicroneedles as a final outer layer. Several different processes can beused to coat microstructures with metal layers, including electroplating(or electrodeposition), electroless plating, sputtering, vapordeposition, and plasma deposition. It is possible to electroplate somealloys, metal oxides, polymers, and composite materials. Depending onthe material that is electroplated, the plating solution can be aqueousor organic.

Electroless plating can be used to deposit metal, oxides, or polymers onvirtually any kind of substrates. Sputtering can only be used to depositthin metal films (from angstroms to nanometers), although sputtering isa fast and inexpensive technique that is convenient to coatnon-conductive samples with seed metal layers for a later step ofelectroplating.

Vapor deposition is preferred over sputtering in the cases wheremicrosmooth metal and oxide films are desired or when common metals donot adhere strongly to the substrates. For vapor deposition, the sampleare placed in a vacuum chamber where the metals are evaporated usingresistive heating or an electron beam. The metal vapors deposit on thecold areas of the vacuum chamber, including the sample surface. Usually,the specimens are coated with a few angstroms of a metal adhesion layerprior to the deposition of the metal or oxide or interest.

Plasma deposition is a technique that can be employed to deposit verythin films (having a thickness in the order of angstroms) of severalkinds of materials on conductive or non-conductive substrates. However,this process typically is slow and expensive. It is normally utilized toprepare films of materials that cannot be handled using themethodologies mentioned above.

One methodology utilizing the principles of the present inventioninvolves fabrication of solid polymeric microneedles usingphotolithography and replica molding. Two different fabrication schemesare described below, and these are illustrated in FIGS. 1 and 2. “FIG.1” consists of FIGS. 1A-1F, and illustrates a process that can producepolydimethylsiloxane (PDMS) molds used in the fabrication of solidmicroneedles that are made of thermally light, or self-curable polymersor by embossing thermoplastics. The first step in the microfabricationmethod of the present invention is to spin-coat a layer that is about20-200 microns in thickness of a photoresist compound (e.g., SU-8) on asilicon wafer, and baking to dryness at 90° C. The silicon wafer is atreference numeral 10, and the photoresist is at reference numeral 12 onFIG. 1A.

The photoresist film is then patterned with posts 14 having a diameterin the range of 10-100 microns, using photolithography, as illustratedin FIG. 1B. The wafer is then silanized with an alkyl chlorosiloxanecompound, then covered with PDMS and cured in an oven at about 60-70° C.for about two hours. This soft lithography step is illustrated in FIG.1C, where the layer of PDMS is at reference numeral 16.

The PDMS negative replica is detached manually from the silicon/SU-8master, as illustrated by the negative replica 16 of FIG. 1D. Naturally,this detachment operation can be automated.

The PDMS structure is then filled under a vacuum with a photocurablepolymer or a prepolymer material, such as epoxy known as UVO-110 under avacuum. This structure is irradiated with ultraviolet light for twohours using a mercury lamp, or other ultraviolet light source to curethe prepolymer 18, in a soft lithography process step. This isillustrated in FIG. 1E, in which the prepolymer is at reference numeral18. Finally, the microneedle structure is separated from the mold,leaving a microneedle array 18 made of polymer as seen in FIG. 1F.

As an alternative methodology, silicon microstructure array mastersprepared using deep reactive ion etching (DRIE), or metallicmicrostructure array masters (prepared using, e.g., LIGA techniques)could be employed instead of the SU-8 photoresist masters to manufacturepolymeric microneedles as shown in FIG. 1. This alternative methodologyis illustrated in “FIG. 2,” which consists of FIGS. 2A-2E. In FIG. 2A,the silicon microstructure array master is illustrated at the referencenumeral 20. As noted above, instead of a silicon structure, themicrostructure could be made of a metallic substance.

The silicon structure 20 is then silanized and covered with PDMS at 22,as seen in FIG. 2B. After being covered with the PDMS material, thestructure is cured in an oven at about 60-70° C. for about two hours.

The PDMS negative replica is detached from the silicon or metallicmaster 20, leaving the negative replica structure 22, as viewed in FIG.2C. The PDMS structure 22 is then filled with a photocurable polymer at24, as seen in FIG. 2D. This photocurable polymer is then exposed to alight source, such as an ultraviolet light source from a mercury lamp.This cures the polymer, and the microneedle apparatus is then separated,leaving the microneedle array 24, as viewed in FIG. 2E. An example of anultraviolet-curable polymer is a compound known as Uv-114, manufacturedby Epoxy Technologies Inc.

The process described in FIG. 1 can be modified to generate freestandingphotoresist microneedle devices, examples of which are illustrated inFIGS. 3 and 4 with respect to their construction techniques. “FIG. 3”consists of FIGS. 3A-3E. An oxidized silicon wafer at 30 includes a toplayer of PDMS at 32, which is coated with a layer of photoresistmaterial at 34, as viewed in FIG. 3A. This structure is baked to drynessand cured with ultraviolet light to obtain a solid film of the curedphotoresist material at 36 (see FIG. 3B). An example of this photoresistmaterial is SU-8. The structure of FIG. 3B is coated again withphotoresist, in this case a layer 38 in the range of 20-200 micronsthick. This structure is baked to dryness at approximately 90° C.,providing the structure of FIG. 3C in which the second layer ofphotoresist is illustrated at the reference numeral 38.

Microneedles are formed in the second layer of photoresist 38 by aphotolithography technique using a transparency mask patterned with dotshaving a diameter in the range of 20-100 microns. This provides thestructure of FIG. 3D, in which solid microneedles at 40 are formed in anarray-type structure.

The microneedle structure is separated from the wafer by dissolving a“sacrificial layer” with an appropriate reagent, in which the PDMS layer32 is decomposed with tetrabutylammonium fluoride (TBAF) andtetrahydrofuran, leaving behind the microneedle array structure 40 ofFIG. 3E.

An alternative methodology for generating a freestanding photoresistmaterial microneedle array is described in connection with “FIG. 4,”which consists of FIGS. 4A-4E. In FIG. 4A, an oxidized silicon wafer 30which includes a layer of silicon oxide at 42, is coated with a layer ofphotoresist material 34 and baked to dryness. The photoresist layer 34is exposed without using a mask and cured, which is illustrated at thereference numeral 36 in FIG. 4B. The wafer structure is then coated witha second layer of photoresist material at 38 and baked to dryness atabout 90° C., which is illustrated in FIG. 4C.

Microneedle-like structures are formed in the second photoresist layerby a photolithography procedure using a transparency mask that ispatterned with dots having a general diameter in the range of 20-100microns. This is the structure illustrated in FIG. 4D, in which the toplayer 44 is the second photoresist layer that has microneedle structuresprotruding upwards in the figure. The wafer structure is then immersedin hydrofluoric acid (e.g., 10% solution) to detach the polymericstructure from the silicon substrate. This provides the separatemicroneedle (polymeric) structure at 44, as illustrated in FIG. 4E. Thesilicon oxide layer 42 acts as a sacrificial layer by dissolving orotherwise decomposing in the hydrofluoric acid.

The array of solid microneedles in FIGS. 3E at 40 and 4E at 44 can beconverted into “hollow” microneedles by various techniques. One wellknown technique is laser ablation, which would essentially bum holesthrough the centerline (or approximately near the centerline) of each ofthe cylindrical microneedle structures.

One aspect of the present invention is to create microneedle arrays thatinclude individual microneedles that exhibit a “high aspect ratio.” Theoverall length of a microneedle divided by its overall width is equal tothe aspect ratio. If a microneedle is 200 microns in length, and itswidth (or diameter if it is circular) is 50 microns, then its aspectratio is 4.0. It is desirable to use a relatively high aspect ratio ofat least 3:1, although creating such structures can be difficult.

The microneedles are so tiny in actual size (especially in the smallerwidths or diameters) that it is not an easy task to make themsufficiently strong to penetrate the stratum corneum of skin withoutbreaking. So there is a trade-off; one cannot merely make themicroneedles “thicker” (or wider), because there needs to be some openarea between each of the microneedles in the array to allow the tips ofthe microneedles to actually penetrate the outer skin layer. This aspectof the use of microneedles is described in detail in a patentapplication that is assigned to The Procter & Gamble Company, under Ser.No. 09/328,947 which was filed on Jun. 9, 1999, and titled“Intracutaneous Microneedle Array Apparatus.” This patent application isincorporated herein by reference in its entirety.

At the same time, one cannot merely make the microneedles shorter todecrease the chance of their being broken upon insertion into skin. Theindividual microneedles should be longer than the thickness of thestratum corneum, or they will not sufficiently increase the permeabilityof the skin to the fluid of interest. These constraints call for astructure that is relatively high in aspect ratio in most instances(such as 3:1, noted above).

Two different methodologies for fabricating hollow microneedles areillustrated in FIGS. 5 and 6, and are described immediately below. “FIG.5” (which comprises FIGS. 5A-5F) starts with a silicon wafer at 50 witha top layer of photoresist at 52 (see FIG. 5A). One preferredmethodology for creating this structure is to use a spin-coatingprocedure to apply a layer of photoresist material that is in the rangeof 20-200 microns thick on the silicon wafer 50. This structure is bakedto dryness at approximately 90° C., and then the photoresist 52 ispatterned with hollow cylinders by use of a photolithography procedure,which results in the structure of FIG. 5B. In FIG. 5B, the photoresistmaterial has been formed into multiple hollow tubes at 54, in which eachof these hollow tubes comprises a hollow cylinder having a wall 58 andan open hollow space at 56 within these walls 58.

The structure is then silanized with an alkyl chlorosiloxane compound,then covered with PDMS under a vacuum, and cured in an oven in the rangeof 60-70° C. for approximately two hours in a soft lithography processstep. This provides the structure seen in FIG. 5C, in which the PDMSlayer is designated by the reference numeral 60.

The PDMS mold is separated from the photoresist master, therebyproviding the structure 60 by itself, as seen in FIG. 5D. This structure60 will be used to obtain plastic “microcups.”

In FIG. 5E, the PDMS mold 60 has been inverted with respect to FIG. 5D.This PDMS mold 60 is now filled with a prepolymer material 62, and thisprepolymer is cured with some type of heat energy or withelectromagnetic radiation, such as ultraviolet light in another softlithography process step. Once cured, the prepolymer material 62 isdetached from the mold 60, thereby leaving behind the structure 62 asseen in FIG. 5F. As can be seen in FIG. 5F, polymeric microneedles areformed as part of the structure 62, in which each of these microneedleshas the form of a “microcup” 64. These microcups include an outercylindrical wall 68 and a center open volume 66. Of course, thesemicrocups could be made into “microtubes” or other type of hollowmicroneedle by use of laser ablation, or by some other technique, ifdesired.

In the procedure illustrated in “FIG. 5,” the hollow microneedles ormicrocups were formed using PDMS molds. As an alternative methodologyfor fabrication, photolithography of a photoresist mounted on asubstrate covered with a sacrificial film could be utilized, as will nowbe discussed in reference to “FIG. 6,” which consists of FIGS. 6A-6E.

Starting with a silicon wafer 70, having a layer of either PDMS orsilicon dioxide material at 72, a layer of photoresist material 74 isapplied, preferably by spin-coating. This is the structure illustratedin FIG. 6A. This structure is then baked to dryness at approximately 90°C. If PDMS is used for layer 72, it could have a thickness ofapproximately 100 microns, or if silicon oxide is used, its thicknesscould be much smaller, on the order of 500 nm.

After being baked, the structure has the appearance as illustrated inFIG. 6B, in which the silicon wafer 70 and intermediate layer 72 istopped by a cured or “baked” layer of photoresist at 76.

This structure is then coated again with a further layer of photoresistat 78, as viewed in FIG. 6C. This structure is then baked, and patternedwith a transparency mask using photolithography techniques. Thisprovides the structure as viewed in FIG. 6D, in which multiple hollowstructures 82 are formed as part of an overall photoresist layer 80.These hollow structures 82 are also in the form of “microcups,” similarto those disclosed in reference to FIG. 5F.

The microcups 82 each have a cylindrical wall 86, as well as a hollowvolumetric space at 84 within the cylindrical walls 86. This microneedleor microcup array structure 80 can be readily detached from thesubstrate, thereby leaving behind the array structure as viewed in FIG.6E. This could involve dissolving the sacrificial layer 72, which if thesacrificial layer consisted of PDMS would involve TBAF(tetrabutylammonium fluoride) in THF (tetrahydrofuran); if thesacrificial layer consisted of silicon dioxide, then the dissolvingfluid would be 10% hydrofluoric acid.

Wafers that have been coated with sacrificial layers can also be used tofabricate hollow microtubes that can be easily detached from the basestructure or substrate of the microneedle array, upon the application ofsmall forces. Such detachable hollow microneedles or microtubes can beused to open momentary cavities across the stratum corneum of the skin.These cavities are not permanent, due to the natural shedding process ofthe stratum corneum. One methodology for constructing such detachablehollow microtubes is illustrated in “FIG. 7.” “FIG. 7” consists of FIGS.7A-7B and 7X-7Z, but it will be understood that the first three steps ofthis procedure in FIGS. 7X-7Z involve the structures illustrated inFIGS. 3A, 3B, and 3C.

The structure illustrated in FIG. 3C involves a silicon wafer 30, alayer 38 of PDMS material that is baked to dryness. In FIG. 3D, solidmicroneedles were formed using a photolithography process. In FIG. 7A,instead of solid microneedles, hollow microtubes will be formed, andthese structures are indicated at the reference numeral 90.

After the silicon wafer has been covered with PDMS and baked to dryness,photolithography is used to make the hollow tubes 90. Each of thesehollow microtubes consist of a cylindrical wall portion 94, whichencompasses an open volume 92. The microneedles fabricated on the PDMSfilm (i.e., layer 32) do not need any type of treatment prior to skinpenetration, because the adhesion between PDMS and most polymers isrelatively weak. Therefore, the microneedles will fairly easily detachupon penetration into the stratum corneum. This is illustrated on FIG.7B, in which the microtubes 90 are shown in place in the stratum corneumlayer 100. The epidermis layer 102 and the dermis layer 104 are alsoillustrated in FIG. 7B, which of course lie beneath the stratum corneumlayer 100.

An alternative fabrication methodology would be to use a silicon waferthat has a silicon oxide layer 42, such as that provided by thestructure illustrated in FIG. 4C. This alternative fabricationmethodology is illustrated in “FIG. 8,” which consists of FIGS. 8A-8Dand 8X-8Z. It will be understood that the first three process steps inFIGS. 8X-8Z involve structures having the appearance of FIGS. 4A, 4B,and 4C.

The structure of FIG. 4C included a silicon wafer 30, a layer of siliconoxide 42, an upper layer of cured photoresist 36, and a second layer ofphotoresist at 38 that was baked to dryness. In FIG. 4D, thephotolithography process was used to form solid microneedles. However,in FIG. 8A, the transparency mask is used to create hollow microneedlesor “microtubes” by the same type of photolithography process.

In FIG. 8A, the microtubes 90 are very similar in appearance to thoseillustrated in FIG. 7A. Each of the microtubes has a cylindrical outerwall 94 that encompasses a hollow volumetric space 92.

In FIG. 8B, an additional procedure of treating the “sacrificial layer”42 with hydrogen fluoride (at 10%) for approximately two (2) to five (5)minutes will weaken the needle/substrate interface, as seen at theportion designated by the reference numeral 96. In other words, thehydrogen fluoride treatment will tend to etch away a certain portion ofthe silicon oxide layer, and leave behind “break away” portions of thecylindrical walls that will facilitate the detachment of the hollowmicrotubes upon skin penetration. A magnified view of the resultingmicrotube 98 having the “weakened” (or “break-away”) area 96 is providedon FIG. 8D.

One structure that has been successfully tested involves a silicon oxidelayer that is approximately 500 nm in thickness, and covered with aphotoresist material (e.g., SU-8) of about 20-200 microns that have beenbaked to dryness at 90° C. This will produce hollow microtubes ormicroneedles that have a length in the range of about 20-200 microns.

FIG. 8C shows the final result, in which the “break-away” hollowmicroneedles or microtubes at 98 are embedded in the stratum corneum100.

Metallic hollow microneedles can also be constructed usingphotolithography techniques. FIGS. 9 and 10 illustrate some of the stepsfor two different methodologies of fabricating metallic hollowmicroneedles. “FIG. 9” consists of FIGS. 9A-9G while “FIG. 10” consistsof FIGS. 10A-10G.

FIG. 9A illustrates a silicon wafer 110 that has had a photoresist layerspin-coated at 112. An example of photoresist material is SU-8, and thethickness of this material could be in the range of 20-200 microns. Thephotoresist is then patterned with cylindrical holes 116 using aphotolithography process, thereby providing the structure in FIG. 9B inwhich the silicon wafer 110 is now topped by a photoresist layer 114that has a plurality of such cylindrical holes 116. These holes couldhave a diameter in the range of 20-100 microns, or virtually any othersize, as desired for a particular application.

This structure is now silanized and then covered with PDMS material thatis cured for about two hours at approximately 60-70° C. in a softlithography process step. The resulting structure is illustrated in FIG.9C, in which the silicon wafer 110 and photoresist layer 114 are toppedby the cured PDMS 118.

The PDMS negative replica 118 is now removed or detached from thephotoresist master, leaving behind the unitary structure 118 that isillustrated in FIG. 9D.

The PDMS mold negative replica 118 is now coated with a metallicsubstance using sputtering or vapor deposition. This is illustrated inFIG. 9E, in which the PDMS material 118 is coated or plated with a metallayer at 120. One example of this metal coating could be a layer of goldthat is approximately 50 angstroms in thickness.

Another example is to use a layer of nickel, copper, gold, platinum, orsilver having a thickness in the range of 10-30 microns, by use of anelectroplating procedure on the previously coated gold/PDMS structure.This will form an array of metallic needles that can be isolated bydissolving the PDMS layer in a 1 M solution of TBAF in THF, therebyleaving the unitary structure 120 that is illustrated in FIG. 9F.

The structure 120 is the separate metal layer that has been detachedfrom the PDMS mold. This structure 120 includes an array of protrusionsat 122, each of which will become the basis for a hollow microneedle ormicrotube. At this point in the process, the microneedles 122 areessentially “closed” and have the form of “microcups” in essence, whenviewed from above. Of course, when viewed from below, these closedmicroneedles 122 essentially act as liquid tight microneedles that havethe appearance of solid microneedles.

These tubular microneedles 122 are now “opened” by polishing the closedends by one of several possible techniques, thereby leaving behind anarray of hollow microneedles in a unitary array structure 124 that isillustrated in FIG. 9G. Each of the hollow microneedles or “microtubes”122 includes a cylindrical wall 128 that surrounds a hollow volumetricspace 126 that, in this illustrated embodiment, supplies a tubularpassageway or through-hole from one surface of the unitary structure 124to the opposite side of that same structure. The polishing techniquedescribed above could be as simple as using sandpaper on the surfacewhere the closed end 122 existed in FIG. 9F, or it could be some type ofmilling or grinding operation, or finally some non-mechanical techniquecould be used, such as a laser beam to burn away or vaporize the closedend by laser ablation.

The microneedle arrays could be separated by hand from the PDMS moldsand the metallic structures could be synthesized using electrolessplating techniques. The molds could be reused if the structures aredisconnected by hand. Moreover, the polishing step could be avoided ifthe tips of the PDMS/gold posts (at 122) were earlier stamped with anon-conductive material such as thiol monolayer or a polymer, or werepeeled off using adhesive tape.

An alternative technique for creating metallic microneedles isillustrated in FIG. 10. Starting at FIG. 10A, a silicon wafer 110 thathas had a photoresist layer spin-coated at 112 is illustrated (similarto FIG. 9A). An example of photoresist material is SU-8, and thethickness of this material could be in the range of 20-200 microns. Thephotoresist is then patterned with cylindrical holes 116 using aphotolithography process, thereby providing the structure in FIG. 10B inwhich the silicon wafer 110 is now topped by a photoresist layer 114that has a plurality of such cylindrical holes 116. These holes couldhave a diameter in the range of 20-100 microns, or virtually any othersize, as desired for a particular application.

This structure is now silanized and then covered with PDMS material thatis cured for about two hours at approximately 60-70° C. in a softlithography process step. The resulting structure is illustrated in FIG.10C, in which the silicon wafer 110 and photoresist layer 114 are toppedby the cured PDMS 118.

The PDMS negative replica 118 is now removed or detached from thephotoresist master, leaving behind the unitary structure 118 that isillustrated in FIG. 10D. The PDMS negative replica 118 of FIG. 10D isnow used in a vapor deposition procedure, and then a procedure wherepolymer is electroplated. The vapor deposition could involve chromium orgold, for example. This would lead to the structure 118 of FIG. 10E, inwhich the plated polymer layer is at 130.

This particular procedure could also be modified to construct taperedmicroneedles by overexposing the photoresist master and then fabricateplastic hollow microneedles by electrodepositing the polymers, such asthe layer 130 of plated polymer material. Such polymer materials thatcan be electroplated include POWECRON® acrylic epoxies (manufactured byPPG Industrial Coatings of Pittsburgh, Pa.), and EAGLE 2100®(manufactured by The Shipley Company of Marlboro, Mass.

The polymer microneedles are separated from the PDMS mold, therebyleaving behind the unitary structure 130 of FIG. 10F. At this point, theprojections that will eventually become tubular microneedles are“closed,” as viewed at 132 on FIG. 10F. Therefore, a procedure isperformed to “open” the microneedles, by use of some type of polishingtechnique, similar to that described above in reference to FIG. 9G. Thisprovides the structure 134 illustrated in FIG. 10G. The microneedlearray structure 134 includes hollow microneedles or “microtubes,” eachof which consists of a cylindrical wall 138 that encompasses an openvolumetric space 136 that extends from one surface to the other of themicroneedle array 134.

“FIG. 11” illustrates a fabrication technique by which microneedles areconstructed by curing polymers that are sandwiched between complimentaryPDMS structures. “FIG. 11” consists of FIGS. 11A-11K, and beginning atFIG. 11A a silicon wafer 140 is spin-coated with a photoresist material142, such as SU-8. A second wafer 150 is also spin-coated with aphotoresist compound 152, as illustrated in FIG. 11E. The photoresistlayer 142 thickness is approximately 175 microns for the wafer 140 ofFIG. 11A, while the thickness of the photoresist layer 152 isapproximately 200 microns on FIG. 11E.

These structures are now patterned using a photolithography process, andan array of holes are formed in the photoresist layer 142, which isillustrated on FIG. 11B by the holes 146, which are bounded by theremaining portions of the photoresist at 144. The separation of theseholes is approximately 300 microns, and these cylindrical holes have aheight of about 175 microns, and a diameter of about 50 microns.

An array of posts 154 are formed from the photoresist 152 by use ofpatterning and photolithography techniques, and these posts have aseparation of approximately 300 microns with a height of approximately200 microns and a diameter somewhat less than 50 microns. See FIG. 11F.After the post 154 and holes 146 are formed on their respectivestructures, both wafers are silanized, covered with PDMS or anequivalent material, and cured at approximately 60° C. for about twohours using soft lithography. This provides the structures illustratedin FIGS. 11C and 11G, in which the PDMS layer 148 protrudes into the“hole” spaces 146 that are between the photoresist structures 144, andthe PDMS layer 156 on FIG. 11G, which surrounds the post 154.

The specimens are now cooled to room temperature, and the PDMS replicasare detached from the wafers, thereby providing the structures 148 and156, as illustrated in FIGS. 11D and 11H, respectively. One of thesereplica structures (preferably the structure 156 having the “holes”) isnow coated with a relatively thin layer of a prepolymer material, suchas polyurethane (PU), epoxy, polymethyl methacrylate (PMMA), bonesuturing materials, dental polymers, or other similar prepolymercompound. The two structures 148 and 156 are now aligned, in which theposts now resident in the structure 148 are aligned with the “holes”resident in the structure 156. The result is illustrated in FIG. 11I, inwhich the replica structure having “posts” 148 is fitted atop thereplica structure having the “holes” at 156, and in which the aboveprepolymer material 160 is placed between these two replica structures148 and 156. Once they are aligned, they are pressed, or held together,and cured as appropriate, using heat energy or perhaps electromagneticenergy, such as ultraviolet light or visible light.

The two PDMS mold replicas 148 and 156 are now separated and the nowcured polymer material 160 is separated from both of these moldreplicas. This provides the structure illustrated in FIG. 11J, in whichthe cured polymer array 160 consists of multiple posts or protrusions at162. These posts/protrusions 162 are not solid, but are hollow, and havea form somewhat similar to a “microcup” as described above. As viewedfrom above in FIG. 11J, these protrusions would have the appearance ofmicrocups, although when viewed from below, they would have theappearance of solid posts or microneedles.

The purpose of this structure is not necessarily to create solidmicroneedles or microcups, and therefore, the closed ends at 162 ofthese protrusions are opened by some type of polishing procedure,thereby forming hollow microneedles or microtubes. Thesemicroneedles/microtubes have cylindrical walls at 168 (see FIG. 11K),and the walls 168 surround an empty volumetric space, as illustrated at166. The polishing procedure could be simply the use of sandpaper, or amore sophisticated or automated procedure using a milling machine or agrinder, for example.

Convex or Concave Microneedle Arrays

If desired, the mold material 156 of FIG. 11G can be made of a materialthat has flexibility characteristics. Such a flexible mold can then beused to form microneedle arrays that are convex or concave in overallshape (i.e., the shape of their substrate). Referring now to “FIG. 16”(which comprises FIGS. 16A-16E), the original rectangular shape of themold 156 is illustrated in FIG. 16A, along with a top mold plate 500that is convex and a bottom mold plate 502 that is concave.

In FIG. 16B, the two mold plates 500 and 502 are pressed against theflexible mold 156, which itself takes the overall shape of a concavestructure (as seen from above in this view). An open chamber at 504 isthereby created between the top microstructure portions of the mold andthe bottom surface of the top mold plate 500. A hole 506 in the top moldplate 500 can be used to place fluidic material (such as a moltenplastic or a prepolymer material) into this chamber 504.

The chamber 504 is now filled with a prepolymer material, such aspolyurethane (PU), epoxy, polymethyl methacrylate (PMMA), bone suturingmaterials, dental polymers, or other similar prepolymer compound. Oncethe prepolymer material is in place, it is cured as appropriate, usingheat energy or perhaps electromagnetic energy, such as ultraviolet lightor visible light (one of the mold halves would have to be transparent tothe particular wavelength if curing via light). This is theconfiguration viewed in FIG. 16C.

Once cured, the mold plates 500 and 502 are separated to release thecured polymer material, which has now become a convex microneedle array510. The individual microneedles are designated by the reference numeral512, while the semicircular substrate surface between microneedles isdesignated by the reference number 514. The “inner” surface 516 of thesubstrate is essentially concave, and could be used to form a reservoirto hold a liquid, if desired.

If the mold plates 500 and 502 are made in the opposite shapes—i.e., ifthe top mold plate 500 was made in a concave shape and the bottom moldplate was made in a convex shape—then the resulting microneedle arraywould also be in the opposite shape, i.e., an overall concave shape.This results in a microneedle array 520 that has the appearance asillustrated in FIG. 16E. The individual microneedles are designated bythe reference numeral 522, while the semi-circular substrate surfacebetween microneedles is designated by the reference number 524. The“outer” surface 526 of the substrate is essentially convex.

The use of the above flexible mold has many advantages: a singlemicrostructure mold 156 can be used to manufacture microneedle arraysthat are of various circular arcuate aspects. For example, two differentconvex shapes can be manufactured from the single flexible mold 156,simply by using two different angled plates for the top and bottomplates 500 and 502. Of course, concave shaped microneedles can also bemade from the same flexible mold 156, by use of two opposite shaped topand bottom plates (not shown).

Polymeric Hollow Microneedles

Polymeric hollow microneedles can be fabricated using multilayerphotoresist masters, as illustrated in “FIG. 12,” which consists ofFIGS. 12A-12G. Starting at FIG. 12A, a film 172 of a photoresistmaterial such as SU-8 is spin-coated on a silicon wafer 170, then bakedto dryness at about 90° C. The thickness of the photoresist could be inthe range of 10-100 microns. This photoresist film 172 is then patternedwith cylindrical holes by use of photolithography, thereby resulting inan array of holes having a diameter of about 10-100 microns, asillustrated in FIG. 12B. The holes are represented at the referencenumerals 176, while the remaining photoresist film is represented at174, which bounds these holes 176.

This patterned wafer structure is now coated again with a second layerof photoresist 176, having a thickness of about 10-200 microns, orperhaps thicker if desired, resulting in the structure illustrated inFIG. 12C. The photoresist layer 176 is now patterned with hollowcylinders that are centered on the holes of the bottom layer (originallythe film layer 172) using photolithography techniques.

This photoresist structure is now silanized, covered withpolydimethylsiloxane (PDMS) under a vacuum, and cured for about twohours in the range of 60-70° C. The resulting structure is illustratedin FIG. 12D, in which the final photoresist material has the form of anarray of hollow microneedles, and given the overall designation 180.Each of the microneedles has an outer cylindrical wall at 184, whichencompasses a hollow cylindrical volume 182.

The PDMS material 180 is detached from the silicon/photoresist master atroom temperature, and now becomes a mold itself, which is filled with aprepolymer such as polyurethane (PU), epoxy, polymethyl methacrylate(PMMA), bone suturing materials, or dental polymers. This now has theform of the structure 190 on FIG. 12E. As can be seen in FIG. 12E,cylindrical “posts” at 192 are formed, which are surrounded by openareas 194, which become a mold replica for forming microneedles that arehollow and cylindrical. The PDMS mold replica also has relatively flatsurfaces at 196 that will become the substrate substantially flatsurfaces between microneedle positions, and also has a final “bottom”surface (as viewed on FIG. 12E) at 198 that represents the deepestportion of the cylindrical open areas 194.

FIG. 12H provides a perspective view of this structure 190, in which therelatively flat surface 196 represents the largest surface area as seenin this view. The cylindrical posts that protrude the farthest aredesignated at the reference numerals 192, which have the cylindricalouter channels 194 with a bottom surface at 198.

An embossing polymer is now placed on top of this surface, which willbecome the actual microneedle structure after the embossing procedurehas been completed. In general, the embossing polymer would be squeezedagainst the PDMS mold replica 190, although that may not be necessary incertain applications or by use of certain materials. This results in amicroneedle array structure 200, as illustrated in FIG. 12F.

As an alternative to embossing, a prepolymer material could be placedagainst the replica mold structure 190 and cured as appropriate (e.g.,by use of heat energy or electromagnetic energy, such as visible lightor ultraviolet light) in a soft lithography process; and after curingthe microneedle array is separated from the mold 190. This also resultsin a microneedle array structure 200, as illustrated in FIG. 12F.

The microneedle array structure 200 consists of multiple microneedlestructures 202, each having a cylindrical wall at 206, which encompassesa cylindrical volumetric space at 204. These microneedles are “closed”at this point, and take the overall form of “microcups.” The closed endportion of the microneedles is formed by the surface 208 of the arraystructure 200.

Since it may be desired to create hollow microneedles that havethrough-holes, the closed portion 208 can be removed from the arraystructure, which then provides the structure 210 illustrated on FIG.12G. These hollow microneedles or microtubes are indicated at thereference numeral 212, and have outer cylindrical walls 216 whichencompass a through-hole of an open cylindrical shape at 214.

If the embossing procedure is to be used with a PDMS mold, such as thatdescribed above, then the softening point of the polymer to be embossedshould be less than about 400° C. to avoid any significant deformationof the PDMS microstructures of the mold piece 190. Of course, if themold was instead made of a metallic material, then a much highertemperature embossing procedure and material could be used.

The mold structure 190 on FIG. 12E can also be used to directly createhollow microneedles without the need for a milling or grinding procedureto remove the closed portion 208, as seen on FIG. 12F. Referring now toFIG. 121, the surface of the mold structure 190 is covered with anembossing polymer material at 220, and is squeezed under pressure by atop plate (or top mold half) 230. The embossing polymer material isallowed to harden or cure before the top mold half 230 is removed.Hollow cylindrical structures are thereby formed in the embossingpolymer material 220, in which the walls of the cylinders are indicatedat 222, and the internal openings at 224.

FIG. 12J illustrates the molded material after the top mold half 230 isremoved. The new structure 220 continues to exhibit cylindrical openingswhich are now through-holes at 224, each such hole having a cylindricalwall structure at 222. The holes 224 were directly formed during themolding process because the top mold half 230 removed all excessembossable material from the top of the posts 192 of the mold structure190 (see FIG. 12I).

It will be understood that the through-holes and associated wallstructures could have a shape other than cylindrical without departingfrom the principles of the present invention. Certainly these hollowmicroneedles formed in the microneedle array structure 220 instead couldbe elliptical, square, rectangular, or edged in form.

Electrochemical Sensors Inside Microneedles

Macroscale glucose electrochemical sensors consisting of two electrodesimmersed in a conducting media composed of glucose oxidase,electrolytes, and hydrogel are among the most reliable sugar detectorsavailable. In such systems, glucose oxidase converts sugar to carbondioxide and hydrogen, and an electrical signal is generated by thecatalytic oxidation of hydrogen on the surface of a platinum electrode.Microneedle devices that include electrodes can be used aselectrochemical sensors, and also they can be used for iontophoretic orelectrophoretic delivery of drugs in interstitial fluids. Fabricationtechniques to create electrodes that are integrated with the microneedledevices is described in detail below. Procedures for the construction ofsuch microelectrodes on the surface of metallic or polymericmicroneedles is disclosed using vapor deposition techniques.

“FIG. 13” illustrates the fabrication processes and structural designsof such microelectrodes in microneedle structures, and consists of FIGS.13A-13J. In FIG. 13A, a silicon wafer 300 has a spin-coating ofphotoresist 302, which could be SU-8 photoresist having a thickness ofapproximately 50 microns. The photoresist is patterned with a structureillustrated in FIG. 13D. One specific design is illustrated in FIG. 13D,in which the photoresist at 304 has dimensions provided on FIG. 13, andwhich appears on FIG. 13B as an array of such patterned designs.

This patterning procedure preferably involves photolithography, afterwhich the structure is silanized. After that has occurred, the patternedwafer is covered with PDMS, pressed against a flat surface such as aglass slide, then cured at about 60° C. in a soft lithography processstep. The PDMS membrane is illustrated in FIG. 13C after it has beenremoved from the wafer, and is designated generally by the referencenumeral 306. A single structure having this shape is illustrated in FIG.13E, in which the PDMS membrane 306 has an open area of a shape asillustrated at 308.

The structure 306 represents holes or openings 308 in the PDMS membranethat will be used as a mask during a metal vapor deposition procedure.The longitudinal portion 316 of this opening 308, in the relative centerarea of the pattern, is designed to form two microelectrodes inside eachmicroneedle. The larger rectangular segments 318 of the pattern 308 areutilized to construct electrically conductive pads 304 that will connectthe microelectrodes to leads of an electrochemical analyzer. When usingthe dimensions illustrated on FIG. 13D, each of the pads 304 will havedimensions of about 300 microns×700 microns, and the longitudinalportion is represented by a rectangular shape 316 having dimensions ofabout 25 microns by 300 microns.

An array 310 of polymeric or metallic microneedles is prepared, andforms a structure as illustrated in FIG. 13F, by which microneedles 312protrude from one surface of the array structure or substrate 310. Ifthe microneedles are metallic, they can be prepared using thefabrication techniques as described in reference to either FIG. 9 or 10.If metallic microneedles are utilized, a thin film (of approximately5-10 microns in thickness) of an insulating polymer is electroplated onthe surfaces of this array 310, thereby providing a structure asillustrated in FIG. 13G which is coated by an insulative layer ofmaterial. This will lead to a layer of insulative coating at 314 on themicroneedles themselves. Of course, if the microneedle array structure310 consists of an insulative material, then no additional polymer layeris required.

The cured PDMS pattern 306 is now placed upon the planar face of themicroneedle structure 310 and the linear or longitudinal center portions316 of each of the patterns 308 are aligned with each of the microneedlestructures 314. This involves the PDMS layer 306 being placed againstthe top surface of the microneedle array 310, as viewed in FIG. 13H.Once that has occurred, a metal vapor deposition procedure can commence,while the structures are held in place by some type of clamp, tape, ortemporary adhesive.

A layer of metal, such as gold or platinum, is then vapor deposited onthe membrane/microneedle structure in a thermal evaporator, after whichthe PDMS mask 306 is detached from the microneedles, thereby forming amicroneedle array structure 330, as illustrated in FIG. 131. While inthe thermal evaporator, the samples are held at about 30-45° C. withrespect to the metal source to ensure the deposition of metal inside themicroneedles. The needles are filled with the conducting media describedabove (e.g., hydrogel, electrolytes, or glucose oxidase) before they areused as glucose sensors. Each of the resulting microneedles 314protrudes from the planar substrate 310, and each of these hollowmicroneedles 314 includes an electrode structure 320 that runs at leastpart way down the inside cylindrical wall surface 322 of themicroneedles 314. The electrode structure 320 is electrically connectedto a pad 306, as illustrated in FIG. 131.

A more detailed view of this structure 330 is provided in FIG. 13J, bywhich the microneedle array 330 includes an upper planar surface orsubstrate 310, an electrically conductive pad 306, an electrode 320 thatis both connected to the pad 306 and runs down the inside surface of thecylindrical wall 322 that forms the inner hollow surface of themicroneedle itself.

The fabrication of a PDMS mask and the vapor deposition of metallicmaterial is not necessary if the polymer to be electroplated is aphotoresist. In this situation, the electrodes and pads can beconstructed by use of photolithography techniques. Not only are verysmall electrode structures able to be constructed by photolithography,but in addition larger electrode structures can be formed, also usingphotolithography. Such an example is illustrated in FIG. 14.

In FIG. 14, electrode “bands” are formed on a microneedle arraystructure, rather than using independent electrode systems for eachmicroneedle as illustrated in FIG. 131. In FIG. 14, a large number ofmicroneedles 352 are formed on a microneedle array 350. The top planarsurface 354 shows that different materials can be applied thereto. Forexample, a “working electrode” 360 can be formed on one portion of thisstructure 350, and can encompass a number of the microneedles 352,including the inner cylindrical hollow surfaces of these microneedles352. A “counter electrode” 364 can be formed in a different area, andcan also encompass many such microneedle structures 352. Finally, a“reference electrode” 362 can be formed using a third set ofmicroneedles 352. Each electrode area is electrically conductive betweeneach of its individual microneedles 352 by an electrically conductivemetallic surface along the top of the substrate at 354. Such electrodebands could alternatively be formed on the opposite side of themicroneedle array. In other words, electrode bands could be formed oneither the top or the bottom of the microneedle array 350 when hollowmicroneedles are used.

On the other hand, solid microneedles could be used at 352, if desired.In that circumstance, the solid structure 352 could have the form ofcylindrical posts that are coated by electrically conductive metalwithin the various bands 360, 362, or 364. If the microneedles startedas hollow structures, their inner diameters could be filled (or at leastplugged) by the metal of the electrode bands 360, 362, or 364.

Glucose sensors could also be formed using polymeric microneedles, asmentioned above. The polymeric microneedles can be formed in the samemanner as metallic microneedles, in which the initial specimen iscovered with a PDMS mask prepared as described in reference to FIGS.13A-13C. The electrodes can then be formed by metal vapor deposition ina thermal evaporator, or perhaps in a sputtering machine.

Using the principles of the present invention, it is also possible tomake a mold insert that can create a microneedle having a sharp tipusing photolithography techniques. “FIG. 15” illustrates some of thefabrication steps in such a procedure, in which “FIG. 15” consists ofFIGS. 15A-15L. Starting with a silicon wafer 400 that has a top layer402 of either PDMS material or silicon oxide material, the waferstructure is coated with a layer of photoresist 404. This layer 404 isbaked to dryness and then patterned using a transparency mask and anelectromagnetic light source (such as an ultraviolet light source) so asto create locally a relatively small cylindrical hole, as seen at 410 inFIG. 15B. In FIG. 15B, the photoresist layer 404 is now shown as twohalves, at 406 and 408.

After this first photolithography step, a second layer of photoresistmaterial 420 is now placed atop the structure, as viewed in FIG. 15C.After this photoresist 420 has been baked to dryness, it is patternedusing ultraviolet light and a transparency mask to create locallyanother cylindrical opening that is somewhat larger than the first one410. This second cylindrical opening is designated by the referencenumeral 426 on FIG. 15D, and it can be seen as separating thephotoresist material 420 into two halves, 422 and 424. It will beunderstood that this FIG. 15D is a cut-away view, and the opening 426 isactually the further half (from the observer) of a cylindrical innerwall, and therefore, the two “halves” 422 and 424 still make up a singlelayer of photoresist material that has certain openings, such as the oneat 426.

The next step after this second photolithography step is to again placea further layer of photoresist material 430 atop the structure, therebyarriving at the structure illustrated on FIG. 15E. After this new layerof photoresist at 430 has been baked to dryness, it is patterned using alight source and a transparency mask to create locally a somewhat largercylindrical hole, as seen at 436 on FIG. 15F. The photoresist layer 430is now illustrated as consisting of two halves at 432 and 434, which areindeed a single layer.

After this third photolithography step, still another layer ofphotoresist material 440 is placed atop this structure, as viewed inFIG. 15G. In this example, the photoresist layer 440 is much thickerthan any of the earlier photoresist layers 404, 420, or 430.

After the photoresist layer 440 has been baked to dryness, it ispatterned using ultraviolet light and a transparency mask to createlocally a still larger cylindrical hole, as seen at 446 on FIG. 15H. Thephotoresist layer 440 is now shown in two halves at 442 and 444. It willbe understood that certainly more than three intermediate layers ofphotoresist material could be used to create a mold form, as compared tothat shown in FIG. 15H.

In FIG. 151, the mold structure, generally designated by the referencenumeral 450, has been separated from the silicon wafer 400 by dissolvingor otherwise decomposing the sacrificial layer 402 with an appropriatereagent. As noted above, PDMS can be decomposed with TBAF, and siliconoxide or silicon dioxide can be immersed in hydrofluoric acid to causethe detachment.

FIG. 15J shows several of the holes 446 as part of an array of suchholes in the total mold structure 450. Certainly, for any practicalmicroneedle array mold, there would be dozens if not hundreds orthousands of such holes 446 as part of the mold structure 450 in itsentirety.

Now that the mold 450 has been fabricated, microneedles can be formed byuse of injection molding, embossing, or some other type ofmicrofabrication technique, even including microcasting if it isdesirable to create metallic microneedles (although different materialswould have to be used). FIG. 15K shows an arrangement where a plasticstructure generally designated at the reference numeral 460 is placedbetween two mold halves 470 and 472, which act as pressure bases, andalso retain the plastic material 460 within the mold cavities that areavailable in contact with the patterned mold 450. As can be seen in FIG.15K, the plastic material 460 will flow into the shaped holes 446 thatwere created in this mold structure 450. Once detached from the mold, anarray of microneedles is formed, generally designated by the referencenumeral 460. Array 460 includes multiple “sharp” microneedles 462, asviewed in FIG. 15L. As noted above, these “sharp tip” microneedles couldbe of various sizes and shapes, and certainly could be created from morethan three stages of photoresist layers being patterned by use ofphotolithography techniques, without departing from the principles ofthe present invention.

One optional variant in the microneedles described above is to create astructure in which the base material is different from the microneedlestructure material, which allows the designer freedom to createhydrophobic-hydrophilic combinations. Examples of such different typesof materials are as follows: glass, mica, Teflon®, and metalizedsurfaces.

It will be understood that all of the microneedle structures describedabove can be of any length or width, or any inner diameter for hollowmicroneedles or microcups, without departing from the principles of thepresent invention. Certain exemplary dimensions have been disclosedabove, but these are only examples of prototypical units. It will alsobe understood that the microneedles (both solid and hollow) could beconstructed of various shapes other than cylinders, such as ellipticalprofiles, or “edged” microneedles, such as disclosed in a patentapplication that is assigned to The Procter & Gamble Company, under Ser.No. 09/580,780) which was filed on May 26, 2000, and titled“Intracutaneous Edged Microneedle Apparatus.” This patent application isincorporated herein by reference in its entirety.

It will be further understood that the chemical compounds disclosedabove are exemplary for certain prototypical microneedles, and as suchare quite useful, but at the same time other compounds might easily beemployed without departing from the principles of the present invention.For example, the substrate does not always need to be silicon, and thesacrificial layer is not always required to be either PDMS or siliconoxide. Certainly other polymers or plastics could be used than disclosedabove, or other metals.

Another alternative embodiment of the microneedle structures describedabove is to change their properties by a “surface modification”treatment which allows a coating to occur at the molecular level. Toeffect this treatment, the silicon needles can be silanized withreagents to derivatize the surfaces. Typically, such coating would occurafter the microneedles are already formed.

Yet another alternative embodiment would be a plasma treatment of epoxyor other types of polymeric microneedles to impart different surfaceproperties. Again, such treatment would typically occur after themicroneedles have been formed. One such different surface propertiescould be to impart hydrophobic/hydrophilic properties to themicroneedles.

Still another alternative embodiment of the microneedles of the presentinvention is to incorporate carbon fibers or other composite materialsinto epoxy or polymeric needles and perhaps the substrate. The use ofharder materials could reinforce the polymeric needles and make themmore rigid. One example would be to add carbon fibers or compositematerials into a photoresist compound, such as that illustrated in FIG.3A at 34. This would lead to the microneedles at the microneedle array40 in FIG. 3D to be more rigid. The entire microneedle structure couldbe hardened, if desired, by incorporating carbon fibers or othercomposite materials into all of the materials used to manufacture thestructure, including the base or substrate.

As an alternative to the above, the substrate materials utilized increating the microneedles of the present invention could be made moreflexible, although it normally would be preferred to keep themicroneedles themselves as a rigid structure. One methodology forcreating substrates that are more flexible is to add microchannels andgrooves to the substrate, thereby making the fairly rigid material havesome “bendability” while not being prone to fracture.

Another alternative “flexible” embodiment is to create more flexiblemicroneedles themselves, in which the microneedle structures would besufficiently rigid to break the skin, but still have some flexibilitythat would be quite useful for continuous sensing and dispensingsystems. This would be the opposite of the break-away microneedlesdisclosed above, for example in FIGS. 8B and 8C. These flexiblemicroneedles would be achieved by using materials such as elastomers andpolyurethanes that are moldable or embossable. Examples of suchelastomers are silicones.

Yet another alternative “flexible” embodiment is to create a microneedlestructure in which the entire structure is at least somewhat flexible,although the flexibility properties of the needles could be differentthan the flexibility properties of the base. An example of this is wherethe needles, or at least their tips, are made of a first material(having a first flexibility or elasticity property) and thebase/substrate is made of a second material (having a second flexibilityor elasticity property). For example, the base/substrate could be madeof nylon while the microneedles are made of silicone or polyurethane,thereby providing a microneedle array that has a barely flexiblebase/substrate but a much more flexible set of needles.

A further alternative embodiment for the microneedles of the presentinvention is to place a final outer layer of a metal coating over themicroneedle structures. For solid microneedles, this would have theappearance as viewed in FIG. 9E, which illustrates plated metal over aPDMS replica that itself could become a microneedle array. Such astructure has the advantage of fairly quick manufacturing, whileremaining accurate at the microstructure level and while having thesurface properties of a structure formed entirely from metal. Thethickness of the outer metal coating can be controlled by a vapordeposition or electroplating process.

Several different processes can be used to coat microstructures withmetal layers. The most common techniques are electroplating (orelectrodeposition), electroless plating, sputtering, vapor deposition,and plasma deposition. In an electroplating process, a conductive sampleis used as the cathode (or the anode for electrooxidation reactions) ofan electrochemical system that contains ions of the metal that will bedeposited on the substrate (e.g., Ni, Cu, Ag, Au, Pb, Sn, Al or Pt).

It is also possible to electroplate some alloys (e.g., Pb/Sn, bronze, orsteel), metal oxides (e.g., titanium or aluminum oxides), and polymers(e.g., polyphenols or polypyrroles). Depending on the material that iselectroplated, the plating solution can be aqueous (e.g., Ni, Cu, Ag,Au, Pb, Sn, or Pt) or organic (e.g., polymers, Al, or titanium oxides)and may contain stabilizers, brighteners, and wetting agents. In manyinstances, electroplating allows the formation of crystalline films asthick as 1-2 millimeters. If the sample to be electroplated is notelectrically conductive, it must be coated with a thin film of aconductive material (e.g. metals or conductive polymers) prior toimmersion in the electrochemical cell.

Electroless plating can be used to deposit metal, oxides, or polymers onvirtually any kind of substrates. In this case, the sample is cleanedusing organic solvents (e.g., acetone or methanol) and/or mineral acids(e.g., hydrofluoric or nitric acid), activated for metal depositionusing a metallization catalyst (e.g., palladium chloride), and immersedin a solution including electron donor species (e.g., phosphate ions)and the material that is going to be plated. The thickness of theelectroless plated films can range from a several angstroms to a fewmillimeters and is affected by the pH of the plating solution, time ofreaction, and concentration of the chemicals involved in the depositionprocess.

Sputtering can only be used to deposit thin metal films (from angstromsto nanometers) on either conductive or non-conductive substrates. In thesputtering instrument, gas ions (e.g., Ar) are used to vaporize theatoms of a metal source (e.g., Au, Pt, Cr, Ag, or Cu) that are thendirected towards the sample surface for deposition using an electricfield. Sputtering is a fast (e.g., taking only a few minutes) andinexpensive technique that is convenient to coat non-conductive sampleswith seed metal layers for a later step of electroplating, including thefabrication of microelectrodes (employing a mask, such as the mask 306in FIG. 13H), provided that there is good adhesion between the metalfilm and the substrate.

Vapor deposition is preferred over sputtering in the cases wheremicrosmooth metal and oxide films are desired (having a coatingthickness on the order of angstroms or nanometers) or when common metals(e.g., Au, Ag, Al, or Cu) do not adhere strongly to the substrates. Forvapor deposition, the sample are placed in a vacuum chamber where themetals are evaporated using resistive heating or an electron beam. Themetal vapors deposit on the cold areas of the vacuum chamber, includingthe sample surface. Usually, the specimens are coated with a fewangstroms of a metal adhesion layer (e.g., Cr or Ti) prior to thedeposition of the metal or oxide or interest. This process is generallycompleted in one or two hours and is employed for the fabrication ofelectrodes, seed layers for electroplating processes, and the depositionof thin layers of metal on three dimensional samples (in which thesample can be rotated at an angle in the vacuum chamber).

Plasma deposition is a technique that can be employed to deposit verythin films (having a thickness in the order of angstroms) of severalkinds of materials (e.g., organic compounds, polymers, oxides, or metalprecursors) on conductive or non-conductive substrates. This process isslow and expensive. It is normally utilized to prepare films ofmaterials that cannot be handled using the methodologies mentionedabove.

External Channel Microneedles

Solid microneedles can be manufactured with external channels runningalong one or more sides of the elongated walls. For example, FIG. 17illustrates a solid microneedle 600 that has a elongated side wall 610and a top surface 612 at its tip. The length of the microneedle isdesignated by the dimension line 614, which could be in the range of100-500 microns.

An external channel 620 is formed in one side of the wall 610. Thechannel 620 is substantially rectangular in profile in this view, andcould have dimensions (at 622 and 624, respectively) of about 10 micronsby 10 microns. Of course, the channel 620 could be of other dimensions,if desired. Channels can also be made to taper so as to increasecapillary driving forces.

The external channel 620 is preferably in communication with anotherchannel 632 that is in the base structure 630 of the microneedle array.This base channel 632 could be used to transport interstitial fluid, forexample, to a sensor device 640. This sensor device could beelectrochemical or optical in nature, or perhaps could use a differentprinciple of operation.

Groups of solid microneedles having external channels could be formed ofa single microneedle array. On FIG. 18, four such solid microneedles areillustrated at the reference numerals 650, 652, 654, and 656. Theircorresponding external channels are designated by the reference numerals660, 662, 664, and 666, respectively. Note that each microneedle has twosuch external channels on FIG. 18.

Some of the external channels are fluidically joined by channels in thebase structure 690. These base channels are designated by the referencenumerals 670, 672, 674, and 676, respectively. All four of the basechannels 670, 672, 674, and 676 meet at a “collection port” 680, whichcould be a through-hole in the microneedle base structure (or substrate)690. Such collection ports could be located anywhere on the base 690,and the illustrated embodiment of FIG. 18 is merely an exemplarysituation where four such microneedles are grouped to a singlecollection port. Moreover, there could be an individual collection portper microneedle, if desired; such paired microneedles and collectionports would typically be located proximal to one another.

The fluid that traverses the base channels 670, 672, 674, and 676 andexternal microneedle channels 660, 662, 664, and 666 could be travelingin either direction. If sampling interstitial fluid, for example, thenthe collection ports would likely lead to a chamber or reservoir thatwill either have an associated sensing apparatus, or will trap the fluidfor later use or measurement. If dispensing a fluid, for example, thecollection ports would be in fluidic communication with a reservoir thatcontains the drug or active that is to be placed through the outer skinlayer.

The foregoing description of a preferred embodiment of the invention hasbeen presented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed. Obvious modifications or variations are possible in light ofthe above teachings. The embodiment was chosen and described in order tobest illustrate the principles of the invention and its practicalapplication to thereby enable one of ordinary skill in the art to bestutilize the invention in various embodiments and with variousmodifications as are suited to the particular use contemplated. It isintended that the scope of the invention be defined by the claimsappended hereto.

What is claimed:
 1. A method for fabricating microneedles, said methodcomprising: (a) providing a substrate that includes a plurality ofmicrostructures; (b) coating said substrate with a layer of a firstmoldable material that takes the negative form of said plurality ofmicrostructures, and hardening said first moldable material; (c)separating said hardened first moldable material from said substrate,thereby creating a micromold from said hardened first moldable materialcontaining said plurality of microstructures; and (d) applying a secondmoldable material onto said micromold, allowing said second moldablematerial to harden using a soft lithography procedure, then separatingsaid hardened second moldable material from said micromold, therebycreating a microneedle structure from said hardened second moldablematerial having the three-dimensional negative form of said plurality ofmicrostructures of the patterned micromold; wherein said microneedlestructure comprises one of: (a) a plurality of solid protrusions, (b) aplurality of hollow protrusions forming through-holes, (c) a pluralityof hollow protrusions forming microcups that do not extend entirelythrough said hardened second moldable material, or (d) a plurality ofsolid protrusions, each having at least one surface external channel. 2.The method as recited in claim 1, wherein said first moldable materialcomprises PDMS, said second moldable material comprises a prepolymer,and said substrate comprises one of silicon or a metallic substance; andwherein said microneedle structure comprises a polymeric material. 3.The method as recited in claim 1, wherein said substrate is constructedby: beginning with a wafer material, coating said wafer material with atleast one layer of a photoresist material, and patterning saidphotoresist material with a plurality of microstructures by use of aphotolithography procedure, such that said patterned photoresistmaterial comprises said plurality of microstructures; and wherein saidfirst moldable material is processed and hardened by a second softlithography procedure.
 4. The method as recited in claim 3, wherein saidwafer comprises silicon, said photoresist material comprises SU-8, saidfirst moldable material comprises PDMS, and said second moldablematerial comprises a prepolymer; and wherein said microneedle structurecomprises a polymeric material.
 5. A method for fabricatingmicroneedles, said method comprising: (a) providing a substrate thatincludes a plurality of microstructures; (b) coating said substrate witha layer of a first moldable material that takes the negative form ofsaid plurality of microstructures, and hardening said first moldablematerial; (c) separating said hardened first moldable material from saidsubstrate, thereby creating a micromold from said hardened firstmoldable material containing said plurality of microstructures; (d)applying a second moldable material onto said micromold, allowing saidsecond moldable material to harden using a soft lithography procedure,then separating said hardened second moldable material from saidmicromold, thereby creating a microneedle structure from said hardenedsecond moldable material having the three-dimensional negative form ofsaid plurality of microstructures of the patterned micromold; (e)providing a second substrate that includes a second plurality ofmicrostructures, wherein said second plurality of microstructures issubstantially complementary in shape as compared to said first pluralityof microstructures; (f) coating said second substrate with a layer of athird moldable material that takes the negative form of said secondplurality of microstructures, and hardening said third moldablematerial; (g) separating said hardened third moldable material from saidsecond substrate, thereby creating a second micromold from said hardenedthird moldable material containing said second plurality ofmicrostructures; (h) applying a fourth moldable material onto saidsecond micromold, allowing said fourth moldable material to harden usinga soft lithography procedure, then separating said hardened fourthmoldable material from said second micromold, thereby creating a secondmicroneedle structure from said hardened fourth moldable material havingthe three-dimensional negative form of said second plurality ofmicrostructures of the patterned second micromold; and (i) applying alayer of a fifth moldable material upon one of said first or secondmicroneedle structures, placing said first and second microneedlestructure into a face-to-face relationship to thereby sandwich saidlayer of fifth moldable material therebetween, allowing said layer offifth moldable material to harden using a soft lithography procedure,then separating said hardened fifth moldable material from both saidfirst and second microneedle structures, thereby creating a thirdmicroneedle structure from said hardened fifth moldable material havingthe three-dimensional negative form of both said first and secondmicroneedle structures.
 6. The method as recited in claim 5, whereinsaid first and third moldable materials comprise PDMS, said second andfourth moldable materials comprise a prepolymer, said substratecomprises one of silicon or a metallic substance, and said fifthmoldable material comprises a prepolymer; and wherein said first,second, and third microneedle structures each comprises a polymericmaterial.
 7. A method for fabricating microneedles, said methodcomprising: (a) providing a substrate that includes a plurality ofmicrostructures; (b) coating said substrate with a layer of a firstmoldable material that takes the negative form of said plurality ofmicrostructures, and hardening said first moldable material; (c)separating said hardened first moldable material from said substrate,thereby creating a micromold from said hardened first moldable materialcontaining said plurality of microstructures; and (d) applying a secondmoldable material onto said micromold, allowing said second moldablematerial to harden using a soft lithography procedure, then separatingsaid hardened second moldable material from said micromold, therebycreating a microneedle structure from said hardened second moldablematerial having the three-dimensional negative form of said plurality ofmicrostructures of the patterned micromold; wherein said first moldablematerial after hardening exhibits a flexibility characteristic and,therefore, can be deformed to a predetermined extent without breaking;and further comprising: after creating said micromold from saidhardened, flexible first moldable material, deforming said micromoldduring the step of applying the second moldable material onto saidmicromold, thereby creating either a concave or convex micromold.